The anticancer properties of the flavonoid quercetin have not been effectively translated from the laboratory to the clinic, mainly because the conditions under which the flavonoid may benefit patients have not been established. Although extensive data, derived in vitro and in vivo, demonstrate that quercetin is a potent anticancer compound, knowledge of its function as a chemosensitizer is limited, and its clinical utility in treatment of colorectal cancer patients remains unknown. Cell culture studies, including ours, indicate that quercetin potentiates the effects of therapeutic agents by sensitizing the cells to drugs and to radiation. However, the conditions under which quercetin sensitize malignant cells to adjuvant and/or radiation therapies are yet to be established for intact animals. Currently, 5-fluorouracil (5-FU) is widely used to treat advanced colon cancer; however, this agent is toxic to normal cells. We showed that, upon extended exposure, quercetin alone or in combination with anticancer drugs, including 5-FU, substantially and cooperatively inhibited proliferation of colon cancer cells. We also found that the p53 status of colon cancer cells markedly altered the interaction between 5-FU and quercetin, suggesting an essential role for the molecular background of the target cells in such interactions. Based on these findings, we hypothesize that quercetin will enhance the activity of 5-FU on cells with wild-type p53 in both induced and xenograft models of colorectal cancer by: 1) reducing the size and number of arising tumors; 2) inducing molecular effectors of programmed cell death; and 3) suppressing proliferation of cancer cells. The optimum conditions for quercetin to potentiate the efficacy of 5-FU in mice will be established. Therefore, the goal of this study is to determine the interaction between quercetin and 5-FU in mice. Translated to humans, the findings will aid in designing the chemotherapeutic regimens for colon cancer and lead to more favorable clinical outcomes. Advanced colon cancer is difficult to treat. The use of pharmacological doses of flavonoids to sensitize cancer cells to chemotherapeutic agents and radiation would have a great impact on cancer management by reducing the dose of 5-FU needed to kill cancer cells, by reducing toxic side effects, and by preventing development of drug resistance. Additionally, determination of the role of p53 in the drug-flavonoid interaction would aid in decisions for personalized therapy by identifying patients who will benefit from the combination.